Antihistaminic injectable X-ray contrast media



United States Patent ANTlI -IISTAMDIIC INJECTABLE X-RAY CONTRAST MEDIA'Olle Gunnar Anton Olsson, Lazarettet, Lund, Sweden, gssignor toAktiebolaget Leo, Halsingborg, Sweden, a

No Drawing. Application April 16, 1951,

er a No- .21.3

4 Claims. or. 167-95 This invention relates to new compositions ofmatter suitable for use for X-ray contrast purposes and moreparticularly it relates to such compositions of matter in the form of anaqueous solution.

Intravenous injections of water soluble X-ray contrast media containing3.5-diiodo-4 pyridon-N-acetic acid or salts of the same are occasionallyfollowed by undesired secondary effects such as bouts of coughing orsneezing, flashing of the face and neck, decrease'i'n blood pressure,vomiting, lacrymatio'n, salivation, urticaria, shock effects andcyanosis and even in severe cases death.

Anattempt to exclude patients where undesired secondary effects might beexpected on the base of anamnesis of allergy'and on the 'base ofprevious tests carried out in a similar manner as the tests foridentifying allergic diseases are of little value, as these precautionsprovide no guarantee that the undesired secondary effects will notreally occur. Furthermore, the exclusion of patients on the base ofanarnnesis of allergy or previous tests may result in' the exclusion ofpatients who might tolerate the injection. According to an article byCrepea, Allanson and de Lambre, New York State Journal of Medicine,1949, vol. 49, part 2, pages 2556-2558, attempts have been made 'toavoidthe undesired secondary effects caused by intravenous injection of3.5-diiodo-4-pyridon-N-acetic acid diethanolamine by previous oraladministration of N.N-dimethyl-N-benzyl-N-(apyridyl)-ethylenediaminehydrochloride or l-phenyl-l- (2-pyridyl)-3-dimethylaminopropan withoutany success. The authors conclude: Premedication with pyribenzamine ortrimeton did not seem to influence the incidence, severity or type ofthe reactions to 3.5-diiodo-4- pyridon-N-acetic acid.

One object of the present invention is to enable3.5-diiodo-4-pyridon-N-acetic acid or its water soluble salts to be usedfor X-ray contrast purposes in such a manner that the above namedundesired secondary effects are avoided or greatly reduced. A furtherobject of the invention is to procure aqueous solutions containing3.5-diiodo-4-pyridon-N-acetic acid or a water soluble salt thereof,which solutions are suitable for use for X-ray contrast purposes byintravenous injection and which are of such a character that the numberof cases in which undesired secondary effects follow the injection isgreatly reduced and the severity of the secondary effects if any isclearly less than in the case when solutions of said contrast medium ofthe kind hitherto known have been administered.

With these objects in view and with further objects in view which willappear from the following I shall now proceed to describe the preferredembodiments of my invention.

The invention consists generally in procuring an aqueous solutioncontaining 3.5-diiodo-4-pyridon-N- acetic acid or salts thereof in aconcentration suitable for use for X-ray contrast purposes together witha clinically applicable antihistaminic substance. It has been found thatthe power of reducing the undesired secondary effects followingintravenous injections of X-ray contrast media of the said type is notlimited to any special chemical configuration, but is a generalproperty, although to a varying degree, of a class of chemically quitedifferent substances having in common their power of producingantihistaminic effects. Excellent results have been obtained with anaqueous solution of 3.5-diiodo-4-pyridon- N-acetic acid diethanolamineand fl-dimethylamino ethyl acetic acid diethanolamine may be substitutedwholly or in part by 3.S-diiodo-4-pyridon-N-acetic acid diethylamme.

Most advantageously the antihistaminic substance is introduced into thesolution in such a proportion which s just sufficient to secure thedesired effect, viz. eliminatmg or reducing the undesired secondaryeffects followm'g intravenous injection of X-ray contrast media of theabove named type. Excellent results are obtained in case the proportionof a salt of 3.S-diiodo-4-pyridon-N-acetic acid and the antihistaminicsubstance is such that a quantity of the solution containing thequantity of the X-ray contrast medium usually or maximally used for onein jection contains at the same time a quantity of the antihistaminicsubstance sufficient to secure an effect if used intravenously in thecombatting of allergic diseases such as urticaria. This means that inthis embodiment of the invention ,d-dimethylamino ethyl benzhydryl otherhydro.- chloride is used in amounts from 20-200 mgs per dosis of theX-ray contrast medium whereas the other antihistaminic substancesmentioned above, i. e., 2-phenylbenzylamino-rnethylimidazolinehydrochloride, N'-pmethoXy-benzyl -N pyridyl-N dimethyl ethylenediaminehydrochloride and N dimethylarnino isopropylthiodiphenylaminehydrochloride are used in amounts from about -400 milligrams per dosisof the X-ray contrast medium. The antihistaminic substance may also beused in smaller amounts in which case, however, the undesired secondaryeffects may not be avoided to the same extent. On the other hand I havenot found it necessary to use the'antihistaminic substances in greaterproportions than those stated above since I have found no surplusadvantage being obtained in the way of eliminating or reducing thesecondary effects of the X-ray contrast medium and the undesiredsecondary eifects of the antihistaminic substances such as dizzinessetc. may then occur.

Instead of hydrochlorides of the antihistaminic substances mentionedabove the free bases themselves may be used with excellent results oraddition salts of the said bases with other suitable organic orinorganic acids than hydrochloric acid. Suitable acids are those whichare innocuous and therapeutically acceptable to the organism, forinstance sulphuric acid and ascorbic acid. Whether used as the freebases or as salts with acids other than hydrochloric acid, theantihistaminic substance is to be used in amounts equivalent to thosestated for the hydrochlorides.

The X-ray contrast medium consisting in salts of 3.5-diiodo-4-pyridon-N-acetic acid is used in the concentration and thequantity normally employed intravenously for diagnostic purposes, i. e.a concentration of 35-70 per cent. In the solution containing theantihistaminic substance the following salts of the X-ray contrast medium may be introduced by Way of example in the proportions mentioned inthe following: diethanolamine salt of 3.5-diiodo-4-pyridon-N-aceticacid: 40.5 per cent and diethylamine salt of3.S-diiodo-4-pyridon-N-acetic acid: 9.5 per cent; or diethanolamine saltof 3.5-diiodo-4-pyridon-N-acetic acid: 70 per cent; or diethanolaminesalt of 3.5-diiodo-4-pyiidon-N-acetic acid: 34-36 per cent.

I have found that the amount of antihistaminic substance necessary tosecure the desired effect is independent of the concentration of thespecific salt of the 3.5- diiodo-4-pyridon-N-acetic acid as well as ofthe total concentration of salts in the solution and furthermore that itis unnecessary to increase the amount of antihistaminic substance beyondthose stated above even in the cases where extraordinary greatintravenous injections of the X-ray contrast medium are given.

Very satisfactory results have been obtained by the injection of anaqueous solution containing 3.5-diiodo- 4-pyridon-N-acetic aciddiethanolamine and fl-dirnethyl- Cases with- Cases with percent Group25325: out secondsecondary secondary p ary efiects effects cfiects Thepatients in groups A and B received an intravenous injection of 20milliliters of an aqueous solution containing 35 per cent W/V of3.5-diiodo-4-pyridon acetic acid diethanolamine, the preparations beingfrom two diiferent manufacturers. The patients in group C received anintravenous injection of 20 milliliters of an aqueous solutioncontaining 35 per cent W/V of 3.5-diiodo-4-pyridon acetic aciddiethanolamine+20 milligrams of B-dimethylaminoethyl benzhydryl etherhydrochloride.

Among the patients in groups A and B were none with auarnnesis ofallergy. in group C patients with anamnesis of allergy were notexcluded. The secondary effects observed in group C were less severethan those observed in groups A and B.

The compositions of matter according to the invention may be prepared inthe following way: An aqueous solution of the contrast medium isprepared in a concentration greater than that desired for the finalcomposition. This solution is thereupon mixed with an aqueous solutionof an antihistaminic substance in such an amount as to secure thedesired concentration of the contrast medium in the resulting mixture.It is very satisfactory to use the antihistaminic substance in such anamount that each intravenous dose of the resulting mixture will containa quantity corresponding to that used intravenously for the combattingof allergic diseases.

No changes in the pharmacologic properties of the compositions of matteraccording to the invention have been observed even if the compositionshave been kept for more than one year.

I claim:

1. As a new pharmaceutical composition for intravenous injection anaqueous solution containing e-dialkylaminoethylbenzhydryl ether and atleast one salt of 3,5-diiodo-4-pyridon-N-acetic acid as an intravenouslyinjectable X-ray contrast medium.

2. A new pharmaceutical composition for intravenous injection as setforth in claim 1, the X-ray contrast medium being at least one aminosalt of 3,5-diiodo-4-pyridon-N-acetic acid.

3. A new pharmaceutical composition for intravenous injection as setforth in claim 1 containing the fl-dialkylaminoethyl-benzhydryl ether inan amount of about 20 to 200 milligrams per dose of the X-ray contrastmedium.

4. As a new pharmaceutical composition for intravenous injection anaqueous solution containing 35% W/V 3,5-diiodo-4-pyridon-N-acetic aciddiethanolamiue and fi-dimethylaminoethyl-benzhydryl ether hydrochloridein such an amount that each intravenous dose of the solution contains 20milligrams of the latter.

References Cited in the file of this patent UNITED STATES PATENTSReitmann Mar. 5, 1935 Taplin Dec. 5, 1950 OTHER REFERENCES

1. AS A NEW PHARMACAUTICAL COMPOSITION FOR INTRAVENOUS INJECTION ANAQUEOUS SOLUTION CONTAINING B-DIALKYLAMINOETHYLBENXHYDRYL ETHER AND ATLEAST ON SALT OF 3,5-DIODO4-4PYRIDON-N-ACETIC ACID AS AN INTRAVENOUSLYINJECTABLE X-RAY CONTRAST MEDIUM.